Patients with type 2 diabetes mellitus are at increased risk of developing coronary artery disease, which in turn is the leading cause of death in this population. Patients with diabetes mellitus and coronary disease need effective treatments for both the metabolic derangements of diabetes mellitus and for the myocardial ischemia due to coronary atherosclerosis. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial used a 2-by-2 factorial design to compare alternative treatment strategies for diabetes mellitus and coronary disease in patients with both conditions.1,2

Clinical Perspective on p 2558

The economic consequences of clinical strategies for diabetes mellitus and coronary disease are also important outcomes. The net costs of a clinical strategy are determined not only by the inherent costs of the intended treatment itself but also by the subsequent costs related to clinical consequences of that treatment. Because the economic outcomes are determined in part by clinical outcomes, they are best compared in the setting of a randomized clinical trial, which provides unbiased estimates of the outcomes of alternative treatments. The goal of this study was to conduct a prospective evaluation of the economic outcomes, including medical costs and cost-effectiveness, of the alternative treatment strategies for type 2 diabetes mellitus and stable coronary disease that were tested in the BARI 2D clinical trial.

Methods

The design of the BARI 2D trial and of the economic evaluation have been described in detail.3,4 In brief, patients with type 2 diabetes mellitus and stable, angiographically documented coronary disease were eligible for randomization. Patients were excluded if they required immediate coronary revascularization or had significant left main disease, a creatinine >2.0 mg/dL, a glycohemoglobin A1c(HbA1c) >13%, or either coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) within 12 months.

Patients were randomly assigned according to a 2-by-2 factorial design to a (1) glycemic management strategy comparing insulin sensitization (with metformin or rosiglitazone or both) versus insulin provision (with insulin or sulfonylurea or both) to achieve the target of HbA1c ≤7.0% and (2) revascularization strategy comparing prompt coronary revascularization combined with intensive medical management versus intensive medical management alone, with coronary revascularization at a later date only if clinically indicated. A key feature of BARI 2D was that before randomization, the responsible physician determined whether CABG or PCI would be used if the patient were assigned to prompt coronary revascularization, and randomization was stratified by the intended revascularization strategy (CABG or PCI). The primary end point of the trial was total mortality, and the principal secondary end point was major cardiovascular events; economic outcomes and cost-effectiveness were secondary end points of the trial. As reported previously, total mortality did not differ significantly in either randomized comparison, but major cardiovascular events were significantly reduced by revascularization in the CABG stratum.1

Patients were enrolled at 1 of 49 clinical sites in the United States, Canada, Brazil, Mexico, the Czech Republic, and Austria; 46 of these clinical sites agreed to assess economic outcomes. Economic data were collected by the staff of the Economic Core Laboratory at Stanford University for 41 sites and by the local study staff at 5 sites. Patients were queried every 3 months on their use of specific medical resources, including hospital admissions, physician visits, outpatient tests and procedures, and prescription medications.

Medical care costs were measured for each patient by applying a standardized cost weight to each medical resource used. Hospital admissions were assigned to a diagnosis related group, and costs were calculated with the use of the fiscal year 2007 weights and the national conversion factor. Physician fees from the 2007 Medicare schedule were used for office tests and physician visits and for inpatient procedures. Prescription drugs were assigned costs on the basis of 2007 average wholesale prices. Indirect costs, such as those related to employment, were not measured in this study. In sensitivity analysis, we converted hospital charges to costs and used medication prices from http://www.drugstore.com.

Cumulative costs and medical utilization over 4 years of follow-up were calculated by an actuarial approach in which surviving patients under observation provided data on costs/utilization incurred during each 3-month follow-up interval, which was then multiplied by the Kaplan-Meier survival rate to estimate mean incremental costs/utilization.5 Costs were expressed in 2007 US dollars and discounted at a 3% annual rate, as is conventional in health economic studies.

Cumulative costs/utilizations were compared on an intention-to-treat basis between the 2 glycemic control strategies (insulin provision versus insulin sensitization) and between the 2 revascularization strategies (prompt revascularization versus optimal medical therapy with delayed revascularization if needed to relieve symptoms). These end points were also compared within the predefined strata according to the mode of revascularization chosen before randomization as most appropriate for the patient (CABG or PCI). Statistical significance was assessed with the use of permutation tests, and confidence limits were calculated with percentiles of bootstrap resamples.

We assessed the effects of baseline clinical factors on cumulative medical costs using multivariable regression, after log transformation of cost. We performed this analysis using costs at 2 years because almost all patients had complete data at that point. The effect of each clinical factor was first tested in a model that adjusted only for the 2 randomization assignments, the stratum of intended revascularization, the length of follow-up, and the country of enrollment. The effect of each baseline clinical factor on cost was subsequently assessed in a multivariable model that adjusted for the other baseline characteristics. We tested for interaction between baseline characteristics and randomization assignment on 2-year costs in a model that included all main effects of baseline characteristics. In view of the multiplicity of factors to be tested, a priori we hypothesized that prior insulin use would have a significant interaction with assignment to insulin provision or insulin sensitization and that the stratum of intended revascularization (CABG or PCI) and history of prior revascularization (none, prior PCI only, prior CABG) would have significant interactions with assignment to prompt revascularization or medical therapy.

Cost-Effectiveness

We assessed the cost-effectiveness of the randomized strategies using survival and cost data from the trial. The incremental cost-effectiveness ratio at time “t” [(CE(t)] was calculated as follows: CE(t)=[Cost(t2)−Cost(t1)]/[LY(t2)−LY(t1)], where Cost(ti) indicates the cumulative cost to time t for patient group i, and LY(ti) indicates the cumulative life-years of survival to time t for patient group i. In a sensitivity analysis, we calculated quality-adjusted life-years of survival with an adaptation of our previously reported method,6 estimating utility on the basis of BARI 2D data on the Duke Activity Status Index, self-reported health status, Canadian Cardiovascular Society class for angina, and health rating.

We assessed cost-effectiveness up to 4 years using observed follow-up data and projected long-term cost-effectiveness using a 2-step procedure.7 The observed mortality for the entire patient cohort, irrespective of randomization, after 1 year of follow-up was compared with the age-, sex-, and race-specific expected mortality from the 2007 US Life Tables. We assumed the excess mortality in the BARI 2D patient cohort would continue and estimated remaining life expectancy for each patient alive at last follow-up (mean, 5.3 years).7 In the base case analyses, we assumed that the differences in medical costs between randomized groups observed between 1 and 4 years would decline linearly over the next 4 years of follow-up and that subsequent follow-up costs would be equivalent. We assessed the variability of the cost-effectiveness ratios using 1000 bootstrap resamplings of the patient population. We tested sensitivity of the cost-effectiveness ratios to different scenarios, including the following: quality adjustment of survival; reduced survival after nonfatal myocardial infarction (by 2 years) and nonfatal stroke (by 3 years); and the assumption that cost differences seen between years 1 and 4 would either persist indefinitely or cease immediately after 4 years. Analyses were performed with the use of SAS 9.1.3 (SAS Institute, Cary, NC) and R 2.4.0.

Results

Of the 2368 patients randomized in BARI 2D, 2246 (95%) were enrolled at sites that provided economic follow-up data. One hundred eighty-two patients at participating sites refused economic follow-up, and 59 patients withdrew before providing any economic data, resulting in 2005 participants. Over subsequent follow-up, an additional 67 patients withdrew, and 33 patients were lost. Follow-up for economic outcomes extended to 1 year for 96% of surviving participants, to 2 years for 88%, to 3 years for 61%, and to 4 years for 34%.

Revascularization Strategies

Four-year cumulative costs of patients randomized to the strategy of prompt coronary revascularization ($75 900) were significantly higher (P<0.001) than those of patients randomized to medical therapy ($65 600). The cost difference between these strategies emerged immediately but narrowed over follow-up from $16 800 at 1 year, to $14 900 at 2 years, $13 000 at 3 years, and $10 200 at 4 years (Figure 1, top). Most of the difference in cost between the randomized strategies was due to the higher initial costs of the assigned coronary revascularization procedure (Table 1), which were only partially offset by subsequently lower costs for medications and cardiovascular testing (Table 1).

Before randomization, the responsible physician chose whether CABG or PCI would be used if the patient were assigned to the prompt revascularization strategy. The cumulative cost was significantly higher (P<0.001) in the patients assigned to prompt revascularization, regardless of whether CABG ($20 300 higher than medical therapy) or PCI ($5700 higher than medical therapy) was selected a priori as the intended method of revascularization. The difference in costs between the randomized strategies narrowed progressively over follow-up in both strata (Figure 2), but the patterns of resource use and cost differed somewhat according to the stratum of intended revascularization (Tables 2 and 3⇓). There were greater differences in hospital days and hospital costs between the patients assigned to prompt revascularization and the patients assigned to medical therapy in the CABG stratum than in the PCI stratum, but there were also greater savings in medication costs (Tables 2 and 3⇓).

Glycemic Control Strategies

Cumulative medical costs among patients randomized to the insulin sensitization strategy ($71 300) were higher than the cost of patients randomized to the insulin provision strategy ($70 200), but this was not significant at 4 years (P=0.81). The difference in cost between the insulin sensitization and insulin provision strategies widened between 1 year ($1200) and 2 years ($2000) of follow-up, then narrowed at 3 years ($1000) and 4 years ($1100) (Figure 1, bottom). The difference in cost between the glycemic control strategies was almost entirely due to the significantly higher cost of diabetes-related medications among patients randomized to the insulin sensitization strategy (Table 4). There were fewer diabetes-related hospitalizations among patients assigned to insulin sensitization but no other significant differences in cost or utilization between the glycemic control strategies (Table 4).

Baseline Factors and Cost

We tested the effect of baseline factors on cumulative costs using a multiple regression model after applying a log transformation to 2-year cost (Table 5). Randomization to insulin sensitization increased cost by 11% at 2 years (P<0.0001). There was a significant interaction (P<0.0001) between assignment to prompt revascularization and the intended mode of revascularization on 2-year cost. In the CABG stratum, prompt revascularization increased 2-year costs by 112% (P<0.0001) compared with medical therapy, whereas in the PCI stratum, prompt revascularization increased costs by 54% (P<0.0001) compared with medical therapy.

Use of insulin at the time of study entry increased costs overall by 22% (P<0.0001), but the hypothesized interaction with randomization to insulin sensitization was not significant (P=0.94). A history of prior coronary revascularization did not affect 2-year cost (P=0.33), and the hypothesized interaction with randomization to prompt revascularization was not significant (P=0.77).

Few of the remaining baseline factors affected medical costs significantly. Baseline HbA1c levels and duration of diabetes mellitus each had a graded effect on 2-year cost (P<0.0001) when tested individually but were not significant predictors of cost after adjustment for other baseline factors (Table 5). Women had 10% higher costs (P=0.002), as did patients with a body mass index of ≥30 (P=0.0008). Costs were increased 8% by microalbuminuria and 16% by macroalbuminuria (Table 5). None of these baseline factors had a significant interaction with treatment assignment.

In the fully adjusted model, randomization assignment, baseline insulin use and dose, race, female sex, body mass index, and albuminuria each had significant, independent effects on cumulative costs (Table 5). Mean cumulative costs over 4 years were increased when the analysis was restricted to the 1279 patients (64%) enrolled in US clinical sites (Table 6) and when hospital costs were estimated with the use of charges and the ratio of cost to charges rather than diagnosis related group reimbursements (Table 6).

Table 6. Within-Trial Cost-Effectiveness of Assigned Strategies Over 4 Years of Follow-Up

Cost-Effectiveness

The incremental cost-effectiveness of treatment strategies was assessed with the within-trial data (Table 6) and also after projecting lifetime outcomes (Table 7). Because the prompt revascularization strategy had a significant interaction with the intended form of revascularization on both clinical outcomes1 and costs, we evaluated its cost-effectiveness separately in the stratum of patients with CABG intended and the stratum of patients with PCI intended.

Within the PCI stratum, medical therapy yielded more life-years of survival over 4 years at lower cost and was preferred over revascularization in 99.9% of bootstrap replications at the $50 000 per life-year added benchmark (Table 6). In the lifetime projection, medical therapy had slightly higher costs ($238 100 versus $237 900) but more life-years of survival (14.03 versus 13.70). The cost-effectiveness ratio was $600 per life-year added in the base case analysis, and the medical strategy was preferred over the revascularization strategy in 95% of bootstrap replications (Table 7; Figure I in the online-only Data Supplement).

Within the CABG stratum, prompt revascularization provided slightly fewer life-years of survival over 4-year follow-up, at significantly higher cost (Table 6). However, in the lifetime projection, CABG increased survival from 12.90 to 13.42 years and increased costs from $210 900 to $235 500, yielding a favorable lifetime cost-effectiveness ratio of $47 000 per life-year added. With the use of a $50 000 per life-year added benchmark, CABG was preferred in 56% of bootstrap replications in the lifetime projection (Table 7; Figure I in the online-only Data Supplement).

Over 4 years of follow-up, the insulin provision strategy had lower costs and higher survival (Table 6). In a lifetime projection of cost and survival, however, the insulin sensitization strategy had slightly higher costs ($239 100 versus $236 800) and survival (13.66 versus 13.61 life-years), yielding an incremental cost-effectiveness of $52 000 per life-year added. This lifetime cost-effectiveness estimate was highly variable in bootstrap replications, with insulin sensitization favored in 51% of replications and insulin provision in 49% with the use of the benchmark of $50 000 per life-year added (Table 7; Figure I in the online-only Data Supplement).

The results of the lifetime cost-effectiveness estimates were not changed appreciably by adjusting for quality of life, by adjusting for reduced life expectancy after myocardial infarction or stroke, or by assuming there were no further differences in costs between randomized groups after 4 years (Table 7). When the cost differences seen between 1 and 4 years of follow-up were assumed to continue indefinitely, however, medical therapy became less attractive in the PCI stratum ($57 000 per life-year added), as did insulin sensitization ($82 000 per life-year added), whereas prompt revascularization in the CABG stratum became more attractive ($12 000 per life-year added).

Discussion

Much of the cost of medical care in the population is generated by the management of patients with chronic illnesses such as coronary disease and diabetes mellitus. Effective treatments for chronic diseases may increase overall medical costs, even after accounting for subsequent savings due to prevention of costly complications. These higher net costs may be acceptable, however, if clinical outcomes are sufficiently improved. The assessment of the value provided by treatments therefore requires measuring both their clinical and economic consequences and weighing these outcomes to assess their cost-effectiveness compared with alternative treatments.

In this study, we found that prompt coronary revascularization was significantly more costly than medical therapy for patients who have coronary disease and diabetes mellitus. The high initial procedural costs of CABG and PCI were only partially offset by later cost savings over 4 years of follow-up, a finding consistent with previous studies. The cost-effectiveness of coronary revascularization in the BARI 2D patient population was more difficult to assess owing to the limited duration of follow-up (4 years) compared with the projected life expectancy of the population (>15 years). The limited time horizon of the trial introduces a bias into the cost-effectiveness estimates of procedures because the full costs are captured but only a portion of the benefits. Lifetime projections of cost-effectiveness can remove this bias but introduce uncertainties due to the model.

Medical therapy was quite cost-effective compared with prompt revascularization among patients in the PCI stratum, in both the within trial analysis (Table 6) and the lifetime projection ($600 per life-year added). These results were robust in bootstrap replications and sensitivity analyses (Table 7), strongly suggesting that a strategy of medical therapy, with delayed revascularization only if clinically indicated, is more economically attractive than a strategy of prompt revascularization with PCI.

This result is consistent with the economic outcomes reported by other randomized trials of PCI and medical therapy in stable coronary disease. In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, the cumulative costs among patients assigned to PCI were $11 000 higher over 3 years of follow-up than those of the patients assigned to medical therapy, and the lifetime cost of PCI patients was projected to be $9500 higher. The cost-effectiveness ratio for PCI compared with medical therapy was $262 000 per life-year added in COURAGE.8 The second Randomized Intervention Treatment of Angina (RITA-2) trial found that costs were significantly higher over 3 years follow-up (by £2685, or $4385) among patients randomized to PCI compared with medical therapy.9 Costs over 1 year of follow-up were higher among PCI assigned than medically assigned patients in the second Medicine, Angioplasty, or Surgery Study (MASS II) trial,10 and in the Trial of Invasive versus Medical therapy in the Elderly (TIME), patients assigned to invasive therapy (mostly PCI) had higher costs over 1 year of follow-up than patients assigned to medical therapy.11 In decision models, the cost-effectiveness of PCI depends primarily on the severity of angina because highly symptomatic patients benefit from relief of angina.12,13 Patients with severe symptoms despite medical therapy were excluded from BARI 2D, however. In patients with stable coronary disease and mild symptoms, PCI was not cost-effective because it did not improve survival and led to much higher costs.

Patients in the CABG stratum had much higher costs after random assignment to prompt revascularization than to medical therapy, driven by the higher initial procedure costs. Patients in the CABG stratum were, however, significantly more likely to be free of major cardiovascular events after revascularization (77.6% at 5 years) than after medical therapy (69.5%). Over 4 years of follow-up, this reduction in clinical events did not increase life expectancy sufficiently to be considered cost-effective by conventional benchmarks. Four years of follow-up is sufficient to capture all the costs of CABG but only part of the benefit, however, and a lifetime projection is necessary to provide a fair perspective for the economic evaluation. These projections suggest that CABG may well be cost-effective compared with medical therapy for patients with diabetes mellitus ($47 000 per life-year added). This estimate was, however, variable in the bootstrap analysis and somewhat sensitive to model assumptions and therefore must be interpreted cautiously (Table 7).

BARI 2D represents, to our knowledge, the first trial-based comparison of the economic outcomes of CABG and medical therapy. The major trials comparing CABG with medical therapy were conducted before economic data were collected alongside clinical data in randomized trials. Decision models suggest that CABG is cost-effective relative to medical therapy among patients with either extensive anatomic disease or severe angina symptoms.12,14 Patients with left main disease, extensive coronary disease, or severe angina requiring CABG were excluded from BARI 2D, however. Patients in the CABG stratum typically had more severe coronary disease, with 3-vessel disease in 53% and reduced left ventricular ejection fraction in 18%.15 Our results are broadly consistent with the earlier decision models that demonstrated CABG to be cost-effective compared with medical therapy in higher-risk patients.12–14

The insulin sensitization strategy in BARI 2D was more expensive than the insulin provision strategy, largely because of the higher cost of thiazolidinediones (Table 4). There was little evidence that the higher cost of insulin-sensitizing drugs was offset by reductions in other cost categories (Table 4) or by fewer clinical complications. The cost-effectiveness of the insulin sensitization strategy was therefore not favorable over the 4-year time horizon of the trial (Table 6) but was more favorable in the lifetime projection (Table 7). This lifetime cost-effectiveness estimate was essentially a “toss-up,” however, because there were insignificant differences in long-term cost and survival between the insulin sensitization and insulin provision strategies (Figure I in the online-only Data Supplement).

The glycemic control strategies tested in BARI 2D differ from the treatments evaluated in other trials, which generally assessed specific drugs or intensive versus conventional management approaches. Several prior studies suggest that intensive treatment to lower a HbA1c target may be cost-effective compared with more conventional management of diabetes mellitus.16–21 In BARI 2D, however, the HbA1c target was the same in both the insulin provision and insulin sensitization strategies. There have been relatively few economic evaluations of the newer thiazolidinediones for patients with diabetes mellitus.22 An economic model based on the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive)23 suggested that use of pioglitazone among patients with type 2 diabetes mellitus and evidence of macrovascular disease may be cost-effective.24 Over 3 years of follow-up, the patients assigned to pioglitazone had higher total costs (by £102, or $167) and greater survival, yielding a cost-effectiveness ratio of £5396 ($8811) per quality-adjusted life-year, with a projected lifetime value of £4060 ($6631) per quality-adjusted life-year. The PROactive trial design differed from that of BARI 2D in several ways, most notably in being a trial of a specific drug rather than a management strategy and in achieving significantly different levels of glycemic control between the study groups.

This study has a number of limitations, the most important of which is that economic follow-up extended only to 4 years, less than the average of 5.3 years of clinical follow-up. Therefore, the within-trial cost-effectiveness evaluation did not capture the full effect of the assigned treatments on patient survival. Although we projected survival and costs to assess lifetime cost-effectiveness, these estimates are subject to various uncertainties and consequently must be interpreted cautiously. Furthermore, other clinical trials in diabetes mellitus have shown that survival differences may become evident only after ≥10 years.25,26 Longer follow-up of the BARI 2D patients, which is under consideration, would clarify the clinical effectiveness and cost-effectiveness of these strategies.

In conclusion, the strategy of prompt revascularization in patients with diabetes mellitus and coronary disease is significantly more costly than the strategy of medical therapy with delayed revascularization as needed. The medical strategy was cost-effective compared with the revascularization strategy in the stratum of patients with less severe coronary disease most suitable for PCI. Within the stratum of patients with more severe coronary disease identified as most suitable for CABG, the revascularization strategy may ultimately provide sufficient clinical benefits to be considered cost-effective.

Acknowledgments

We thank Robert L. Frye, MD, and Sheryl F. Kelsey, PhD, for their support of this study.

CLINICAL PERSPECTIVE

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) clinical trial randomized patients with diabetes mellitus and coronary disease to prompt coronary revascularization versus medical therapy, as well as to strategies of glycemia control based on use of either insulin sensitizers or drugs that increase insulin provision. Mortality over 5 years was not significantly different, but major cardiovascular events were reduced by revascularization in the coronary artery bypass grafting stratum. The present study shows that revascularization increases 4-year cost significantly, by roughly $5700 (percutaneous coronary intervention) to $20 300 (coronary artery bypass grafting), whereas insulin sensitization increases costs by $1100. Medical therapy was highly cost-effective compared with prompt revascularization in the percutaneous coronary intervention stratum ($600/life-year added), suggesting that revascularization can be delayed until clinically indicated in patients with less extensive coronary disease. Revascularization may be cost-effective in patients with more extensive disease amenable to coronary artery bypass grafting, but this result was less certain with the limited follow-up available.

Footnotes

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.912709/DC1.